Duloxetine is a selective serotonin and noradrenaline reuptake inhibitor, therapeutically useful to treat for example depression and urinary incontinence.
Preparation of duloxetine and its intermediate products is described for example in patents EP 0 273 658, U.S. Pat. No. 5,362,886, WO 2004/005239, US 2003/0225153. The basic used reaction is described in the following scheme 1.

Most of the syntheses uses for the reaction already optically active intermediate product of formula II, i.e. (S)—N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine. In case of syntheses of many optically active substances, resolution or obtaining optically pure intermediates leads to better yields than resolving the final products. However, in case of duloxetine, it has turned out that when it is further treated according to Scheme 1 racemization takes place again. The final product obtained in this way is not, therefore, enantiomerically pure and it is necessary to recrystallize it again. Of course, this decreases the yield of the process.
A solution of undesirable racemization in the course of reaction according to Scheme 1 is offered by patent application WO 2004/056795 A1. The authors have chosen a method of preparation of racemic duloxetine and its resolving with a suitable chiral acid. Using this method, they, of course, prevent possible racemization; however, on the other hand, by also processing the undesirable (R)-enantiomer until the final stage they increase losses. In this application, di-p-toluoyltartaric acid is presented as the most suitable acid; in patent application WO 2005/108386 A1, use of one equivalent of this derivative of tartaric acid in resolving racemic duloxetine, i.e. 130 g for 100 g of the base, is mentioned in the Examples.
In the original patents, the reaction according to Scheme 1 was used as catalysts. These bases are relatively costly and when they are used it is necessary to avoid moisture, with which they can react violently.
Application WO 2004/056795 also publishes a method of performing reaction according to Scheme 1, where the use of a phase transfer catalyst allows for the reaction to proceed also with weaker bases such as alkali metal hydroxides.
According to our earlier invention (CZ patent 297560, WO 2006/045255) it is advantageous to use, for preparation of (S)—N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine (duloxetine), the optically inactive (RS)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine of formula III
which is resolved using an optically active acid, preferably D-tartaric acid. The optically active acid is used in the stoichiometric ratio with respect to the substance of formula III. The (S)-enantiomer, is isolated which is further demethylated using alkylchloroformates, whereupon hydrolysis is performed and the substance of formula I is isolated.
Preparation of the duloxetine salt is described in Example 2 (Method 2) of U.S. Pat. No. 5,362,886. The final product is obtained via reaction of concentrated hydrochloric acid with a solution of the duloxetine base in ethylacetate. An inoculating crystal of duloxetine hydrochloride is added to the acidified reaction mixture and the mixture is diluted with a further amount of ethylacetate; after 30 minutes of stirring, the mixture is re-concentrated to the initial volume and then stirred at ambient temperature for 1 hour and at the temperature 0° C. for 1 hour. However, when this procedure was reproduced it has turned out that the resulting duloxetine hydrochloride was not completely colorless but slightly pinkish to brownish, which can result in an impure product. The duloxetine molecule is relatively instable, especially in acidic environment. Considering that duloxetine hydrochloride is usually prepared via neutralization of the base with hydrochloric acid, the crude product can contain various impurities. The method of the final purification is, therefore, very important for obtaining the desired quality of the substance and the desired yield as well.
The present invention provides a complete and very advantageous solution of the preparation of duloxetine.